GKT137831 |
| رقم الكتالوجGC11882 |
GKT137831 (GKT137831) هو مثبط انتقائي NADPH أوكسيديز (NOX1 / 4) مع Kis 140 و 110 نانومتر ، على التوالي.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1218942-37-0
Sample solution is provided at 25 µL, 10mM.
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GKT137831, an orally dual NADPH oxidase 1/4 (NOX1/NOX4) inhibitor with potency in the submicromolar range, could prevent oxidative stress in human aortic endothelial cells induced by hyperglycemia and attenuate the development of atherosclerosis in diabetic mice[1-2]. GKT137831 does not affect NOX2-mediated phagocyte function[3].
In vitro, monolayers of Human pulmonary artery smooth muscle cells (HPASMCs) were propagated in culture and placed in hypoxic conditions for 72 hours. Treatment with graded concentrations of GKT137831 (0, 0.1, 5, 20μM) during the last 24 hours of hypoxia exposure attenuated cell proliferation in HPASMCs in a dose-dependent manner, while administration of GKT137831 throughout the 72 hours of hypoxia attenuated HPASMC proliferation at the 20μM concentration[4]. In primary neonatal rat cardiomyocytes (NRCMs), pretreatment with GKT137831 (5μmol/L, 1h) before Doxorubicin (DOX) treatment attenuated DOX-induced apoptosis[5].
In vivo, in C57BL/6J-background CCl4-induced liver fibrosis WT and superoxide dismutase 1 (SOD1) G37R mutant (SOD1mu) mice, after once-daily intragastric administration of 60mg/kg GKT137831 during the latter half of CCl4 treatment, GKT137831 attenuated liver fibrosis and ROS production in both SOD1mu and WT mice, as well as messenger RNA expression of fibrotic and NOX genes[6]. In Sprague Dawley rats subjected to the AAC-induced hypertensive model, oral gavage administration of GKT137831 (30mg/kg) markedly reduced the ratio of heart weight to body weight (HW/BW), the ratio of left ventricular weight to body weight (LVW /BW), and myocyte cross-sectional area in AAC-induced hypertensive rats[7].
References:
[1] Dong Y, Zhang Y, Li F, et al. GKT137831 in combination with adipose-derived stem cells alleviates high glucose-induced inflammaging and improves diabetic wound healing. J Leukoc Biol. 2024;115(5):882-892.
[2] Demircan MB, Mgbecheta PC, Kresinsky A, et al. Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells. Antioxidants (Basel). 2022;11(3):513.
[3] Gray SP, Jha JC, Kennedy K, et al. Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease. Diabetologia. 2017;60(5):927-937.
[4] Green DE, Murphy TC, Kang BY, et al. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol. 2012;47(5):718-726.
[5] Zheng H, Xu N, Zhang Z, et al. Setanaxib (GKT137831) Ameliorates Doxorubicin-Induced Cardiotoxicity by Inhibiting the NOX1/NOX4/Reactive Oxygen Species/MAPK Pathway. Front Pharmacol. 2022;13:823975.
[6] Aoyama T, Paik YH, Watanabe S, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012;56(6):2316-2327.
[7] Zeng SY, Yang L, Yan QJ, et al. Nox1/4 dual inhibitor GKT137831 attenuates hypertensive cardiac remodelling associating with the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways in the rats with abdominal artery constriction. Biomed Pharmacother. 2019;109:1907-1914.
| Cell experiment [1]: | |
Cell lines | Human pulmonary artery smooth muscle cells (HPASMCs) |
Preparation Method | Monolayers of HPASMCs were propagated in culture and placed in hypoxic (1% O2, 5% CO2) conditions for 72 hours. GKT137831 (0.1-20μM), provided through a material transfer agreement from GenKyoTex, or vehicle (1% DMSO) was added to the culture medium at the onset (prevention regimen) or during the last 24 hours (intervention regimen) of a 72 hours hypoxia exposure regimen. |
Reaction Conditions | 0, 0.1, 5, 20μM; 24h (intervention paradigm) and 72h (prevention paradigm) |
Applications | Exposure to hypoxia increased the proliferation of HPASMCs. Treatment with graded concentrations of GKT137831 during the last 24 hours of hypoxia exposure attenuated cell proliferation in HPASMCs in a dose-dependent manner. Administration of GKT137831 throughout the 72 hours period of hypoxia exposure attenuated HPASMC proliferation under at the 20μM concentration. |
| Animal experiment [2]: | |
Animal models | WT C57BL/6J mice, Superoxide dismutase 1 (SOD1) G37R mutant mice in a C57BL/6 background |
Preparation Method | For the CCl4 model of liver fibrosis, 6-week-old male mice were injected intraperitoneally with CCl4, which was diluted 1:3 in corn oil, or with vehicle (corn oil) at a dose of 0.5μL/g of body weight twice weekly for a total of 12 injections. During the last half of CCl4 treatment, mice were treated with 60mg/kg of GKT137831, or vehicle by intragastric (IG) injection daily. Mice were sacrificed 48 hours after the last CCl4 injection. Mice were sacrificed 21 days after the operation. |
Dosage form | 60mg/kg; intragastric (IG) injection |
Applications | Liver fibrosis was increased in SOD1mu mice, and ROS production and Ras-related botulinum toxin substrate 1 (Rac1) activity were increased in SOD1mu hepatic stellate cells (HSCs). GKT137831, attenuated liver fibrosis and ROS production in both SOD1mu and WT mice, as well as messenger RNA expression of fibrotic and NOX genes. Treatment with GKT137831 suppressed ROS production and NOX and fibrotic gene expression, but not Rac1 activity, in SOD1mut and WT HSCs. |
References: | |
| Cas No. | 1218942-37-0 | SDF | |
| Chemical Name | 2-(2-chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione | ||
| Canonical SMILES | CN(C1=CC=CC(C2=C(C3=O)C(NN3C4=CC=CC=C4Cl)=CC(N2C)=O)=C1)C | ||
| Formula | C21H19ClN4O2 | M.Wt | 394.85 |
| الذوبان | ≥ 39.5mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.5326 mL | 12.663 mL | 25.3261 mL |
| 5 mM | 506.5 μL | 2.5326 mL | 5.0652 mL |
| 10 mM | 253.3 μL | 1.2663 mL | 2.5326 mL |
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Quality Control & SDS
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- Purity: >99.00%
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Average Rating: 5 (Based on Reviews and 7 reference(s) in Google Scholar.)
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